After spinal cord injury (SCI), M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages populate the lesion site. M1 macrophages, which cause neurotoxicity and hamper neuroregeneration, persist in SCI lesions. In contrast, M2 macrophages, which support axon growth and are not neurotoxic, disappear after a few days. This progressive loss of M2 macrophages is thought to be due to the conversion of newly activated microglia and infiltrating monocytes into M1 cells as they respond to pro- inflammatory cues in the acute SCI environment. This phenomenon has so far impeded attempts to harness the regenerative power of M2 macrophages to improve SCI recovery. Therefore, therapeutic strategies that suppress M1 and enhance M2 macrophages in the highly inflammatory SCI environment are actively sought. We have recently identified a specific microRNA (miRNA) required for M1 differentiation. miRNA are small RNAs that post-transcriptionally regulate gene expression networks, contributing to cell differentiation and lineage choice. We predict that specific modulation of this miRNA will reduce the ratio of M1/M2 macrophages after SCI, thereby improving the efficiency and extent of tissue repair after SCI. This hypothesis will be tested in an in vivo model of SCI, using mice deficient for this specific mRNA, and developing a pharmacologic strategy to modulate macrophage phenotype with specific miRNA inhibitors. Since miRNA can be manipulated to treat human disease, these studies will provide the basis for development of promising new therapies. In addition, understanding how this specific miRNA controls inflammation through regulation of the M1/M2 balance will have important implications to regulation of macrophage-mediated inflammation (or immune suppression) in other conditions, such as atherosclerosis, wound healing and cancer. PUBLIC HEALTH RELEVANCE: These studies investigate the role of the small RNA miR-155 in spinal cord injury inflammation, pathology and functional recovery. The effects of macrophage-targeted miR-155 loss in control of inflammation and enhancement of neuroregeneration will be assessed in a rodent model of spinal cord injury. These studies will likely impact therapies for spinal cord injury and other conditions such as atherosclerosis, wound healing and cancer.